This research program includes a number of different approaches to both understand how current antitubercular chemotherapy works using the most modern technologies and to use this information to develop new and improved therapies and therapeutic approaches. Individual projects within this framework are aimed at; (1) understanding the biochemical mode of action of existing front-line antituberculars such as isoniazid, pyrazinamide and ethambutol, (2) understanding the mode of action of various agents in animal models of tuberculosis infection, and (3) understanding the development of resistance within patients undergoing chemotherapy. This knowledge is translated in a number of ways including: (1) the development of second-generation antituberculars based upon the same mechanism of action, (2) development of advanced animal models for preclinical evaluation of new agents, and (3) evaluation of surrogate markers for chemotherapeutic efficacy in patients. Section scientists are directly involved in the synthesis and production of combinatorial libraries of analogues of these drugs to allow the identification of preclinical candidates for improving both the total time of treatment and reducing the period of infectivity of pulmonary tuberculosis patients. Section scientists have been involved in elucidating the mechanism of action of the only new class of antibiotics advanced for preclinical consideration since rifampicin, work that was published in Nature this year. Section scientists have also been involved in understanding the mechanism of action of second-line antituberculars and the evolution of multidrug resistance to a class of compounds used clinically in the developing world, work that appeared in the Proceedings of the National Academy of Sciences this year. TBRS scientists will continue to attempt to understand the mechanism of existing antibiotics and to improve these molecules to facilitate the development of new, more effective, antituberculosis drug regimines.